11 ς 2015 3 28 ομ 2 πέτρος καραγιάννης ηπατίτιδα
TRANSCRIPT
Νέες Εξελίξεις στη Θεραπεία της Χρόνιας Ηπατίτιδας Γ
Πέτρος Καραγιάννης Καθηγητής Μικροβιολογίας / Μοριακής Ιολογίας
Ιατρική Σχολή, Πανεπιστήμιο Λευκωσίας
Targeted Antiviral therapy for hepatitis C
virus infection
By
P. Karayiannis
HEPATITIS C VIRION STRUCTURE:
LIPO-VIRAL PARTICLE
Envelope
Core Electron micrograph
RNA
ApoB
ApoE
VLDL
HEPATITIS C VIRUS GENOME ORGANISATION
Moradpour et al, 2007;5:453-463
SIGNAL PEPTIDE PEPTIDASE
SIGNAL PEPTIDASE
VIRALLY ENCODED PROTEASES
GLYCOSYLATION SITES
LIFE CYCLE OF HEPATITIS C VIRUS: POTENTIAL TARGETS
FOR THERAPEUTIC INTERVENTION
ATTACHMENT
UPTAKE
CORE RELEASE
UNCOATING
TRANSLATION
RNA
REPLICATION
ASSEMBLY
TRANSPORT
RELEASE
Pawlotsky, Hepatology 2006;43:S207-20
Bartenschlager R et al, J Hepatol 2010;53:583-5
REPLICATION CYCLE OF HCV: TARGETS FOR ANTIVIRALS
Cytoplasm
Lumen
ER Membrane
Golgi
Antibodies
Inhibitors
Small Molecules
siRNAs,
Miravirsen
PIs
NIs
NNIs
HTAs
Bode et al, Biol. Chem., Vol. 390, pp. 1013–1032
REPLICATION MACHINERY: MEMBRANOUS WEB
HOST TARGETING AGENTS
Jopling et al, Viruses 2010;2:1382-1393
miR122 binding sites and inhibition
of its action
Miravirsen
Translation
INHIBITORS: POTENTIAL NS3 SERINE PROTEASE/HELICASE
TARGETS AND RESISTANCE MUTATIONS HELICASE
PROTEASE
RNA binding
NTPase site
Membrane binding domain
Zinc
Catalytic site
NH2
Inhibitor
BILN-20611,2 Telaprevir2,3,7
(VX-950)
SCH-64 Boceprevir (SCH-5030345)
ITMN-1916
A156V/T
R155Q
D168A/V/Y
A156S/V/T
A156V/T
R109K
A156S/T
T54A
V170A
A156S/V
Q41R, F43S, S138T, D168A,
S489L,
V23A (NS4A)
NA V36A/M
T54A
R155K/T
A156S/V/T
NA V36A/M, T54A,
R155K/Q/T/M,
A156S, V170A/T,
F43C/S
NA
In v
ivo
In v
itro
DAAs and HTAs IN CLINICAL TRIALS
RIBBON MODEL OF THE HCV POLYMERASE
Active site with bound inhibitor and non-nucleoside
inhibitor (NNI) sites 1 to 4. Palm, thumb and fingers
coloured red, green and blue, respectively.
DRUGS FOR FUTURE TREATMENT
OF CHRONIC HCV INFECTION
Welsch et al, Gut 2012;61:36-46.
Sofosbuvir (Sovaldi)
Hepatitis C virus genome and viral proteins targeted by DAAs
Shinazi et al, Liver Int 2014;34 Suppl 1:69-78
Phase III trials with telaprevir in interferon-naive (ADVANCE and ILLUMINATE)
and interferon-experienced patients (REALIZE)
Soriano V et al. J. Antimicrob. Chemother. 2011;66:1673-1686
Jacobson et al, NEJM 2011;364:2405-16 Sherman et al, NEJM 2011;365:2417-28 Zeuzem et al, NEJM 2011;364:2417-28
Phase III trials with boceprevir in interferon-naive (SPRINT-2) and interferon-
experienced patients (RESPOND-2).
Soriano V et al. J. Antimicrob. Chemother.
2011;66:1673-1686
Poordad et al, NEJM 2011;364:1195-206
Bacon et al, NEJM 2011;364:1207-17
0
20
40
60
80
100
IFN 6m IFN 12m IFN/RBV 6m IFN/RBV 12 m Peg-IFN 12m Peg-IFN/RBV 12m Peg-IFN/RBV/DAA
SV
R (
%)
2001
1998
2011
Standard
Interferon
+ Ribavirin
Peginterferon
1991
+ DAAs
Milestones in Therapy of CHC:
Average SVR Rates from Clinical Trials
Adapted from US Food and Drug Administration,
Antiviral Drugs Advisory Committee Meeting, April 27-28, 2011, Silver Spring MD.
6%
16%
34%
42% 39%
55%
70+%
2014 ???
Non-nucleos(t)idic DAAs undergoing
Clinical trials
Welzel et al, J Hepatol 2014;61:S98-107
Not All Direct-Acting Antivirals Have the Same
Properties
Characteristic Protease
Inhibitor*
Protease
Inhibitor**
NS5A
Inhibitor
Nuc
Polymerase
Inhibitor
Non-Nuc
Polymerase
Inhibitor
Resistance
profile
Pangenotypic
efficacy
Antiviral potency
Adverse events
Good profile Average profile Least favorable profile
*First generation. **Second generation.
Feld JJ, CCO Hepatitis
Alexopoulou & Karayiannis, Ann Gastroenterol 2015;51:1-11
Resistance Mutations induced by DAAs When Used as Monotherapy
Sofosbuvir + PEG + RBV: Treatment-Naive HCV GT 1,4,5,6
NEUTRINO Trial: Design & Results 0 12 24 Week
Sofosbuvir + PEG + RBV N=327 SVR12
Lawitz E, et al. N Engl J Med. 2013;368:1878-87.
Sofosbuvir + PEG + RBV: Treatment-Naive HCV GT 1,4,5,6 NEUTRINO Trial: Results
Lawitz E, et al. N Engl J Med. 2013;368:1878-87.
91 87
0
20
40
60
80
100
Non-black Black
Pa
tie
nts
wit
h S
VR
12
(%
)
248/273
47/54
Race and Cirrhosis status
Jacobson IM, et al. Lancet. 2014;384:403-13.
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1 QUEST-1 Trial: SVR12
N =130 Placebo
+ PEG + RBV
Simeprevir
+ PEG + RBV N = 264 PEG + RBV PEG + RBV
PEG + RBV
Randomized 2:1;
stratified on IL28B and
HCV1 subtype
Week 0 12 48 24 36
80
50
0
20
40
60
80
100
Simeprevir + PEG + RBV PEG + RBV
Pa
tie
nts
(%
) w
ith
SV
R 1
2
210/264
Response-Guided Therapy: Patients with HCV RNA <25 IU/ml at week 4
and <15 IU/ml at week 12 completed
treatment after 24 weeks.
65/130
Jacobson IM, et al. Lancet. 2014;384:403-13.
71
90
49 52
0
20
40
60
80
100
1a 1b
Pa
tie
nts
(%
) w
ith
SV
R 1
2
HCV Genotype
Simeprevir + PEG +RBV PEG + RBV
SVR12 by HCV Genotype 1 Subtype
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1 QUEST-1 Trial: Results
105/147 36/74 105/117 29/56
Jacobson IM, et al. Lancet. 2014;384:403-13.
52
85
53
44
0
20
40
60
80
100
1a (with baseline Q80K) 1a (without baseline Q80K)
Pa
tie
nts
(%
) w
ith
SV
R 1
2
HCV Genotype
Simeprevir + PEG + RBV PEG + RBV
QUEST 2: SVR12 for HCV 1a by Baseline Q80K Status
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1 QUEST-1 Trial: Results
Abbreviations: PEG = Peginterferon RBV = Ribavirin
31/60 16/30 73/86 19/43
Source: Jacobson IM, et al. Lancet. 2014;384:403-13.
94
76
65
78
42
24
0
20
40
60
80
100
CC CT TT
Pa
tie
nts
(%
) w
ith
SV
R 1
2
Simeprevir + PEG + RBV PEG + RBV
QUEST 1: SVR12 by Host IL28B Genotype
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1 QUEST-1 Trial: Results
72/77 29/37 114/50 32/76 24/37 4/17
Jacobson IM, et al. Lancet. 2014;384:403-13.
83 78
58 60
26 29
0
20
40
60
80
100
F0-F2 F3 F4 (Cirrhosis)
Pa
tie
nts
(%
) w
ith
SV
R 1
2
Metavir Fibrosis Score
Simeprevir + PEG + RBV PEG + RBV
QUEST 1: SVR12 by Liver Fibrosis (Metavir Score)
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1 QUEST-1 Trial: Results
152/183 54/90 36/46 6/23 18/31 5/17
Simeprevir in Treatment Experienced Genotype 1 HCV ASPIRE Trial: Results
ASPIRE: SVR 24, by Treatment Regimen
Zeuzem S, et al. Gastroenterol. 2014;146:430-41.
70 66
61 67
72
80
23
0
20
40
60
80
100
SMV 12 wks PR 48 wks
SMV 24 wks PR 48 wks
SMV 48 wks PR 48 wks
SMV 12 wks PR 48 wks
SMV 24 wks PR 48 wks
SMV 48 wks PR 48 wks
Placebo PR 48 wks
Pa
tie
nts
wit
h S
VR
24
(%
)
46/66
Simeprevir 100 mg
43/65 40/66 44/66 49/68 52/65 15/66
Simeprevir 150 mg Placebo
Simeprevir in Treatment Experienced Genotype 1 HCV ASPIRE Trial: Results
ASPIRE: SVR 24, by Prior Treatment Response
Zeuzem S, et al. Gastroenterol. 2014;146:430-41.
46/66 43/65 40/66 44/66 49/68 52/65 15/66
37
9
19
85
57
46
85
75
51
0
20
40
60
80
100
Relapser Partial Responder Null Responder
Pa
tie
nts
wit
h S
VR
24
(%
)
Placebo + PEG/RBV SMV 100 mg + PEG/RBV SMV 150 mg + PEG/RBV
Simeprevir in Treatment Experienced Genotype 1 HCV ASPIRE Trial: Results
ASPIRE: SVR 24, by Prior Treatment Response and GT 1 Subtype
Zeuzem S, et al. Gastroenterol. 2014;146:430-41.
46/66 43/65 40/66 44/66 49/68 52/65 15/66
33
40
13 7
0
33
82
89
39
68
33
56
85 84
56
88
42
58
0
20
40
60
80
100
1a 1b 1a 1b 1a 1b
Pa
tie
nts
wit
h S
VR
24
(%
)
Placebo + PEG/RBV Simeprevir 100 mg + PEG/RBV Simprevir 150 mg + PEG/RBV
Relapser Partial Responder Null Responder
Pawlotsky, Gastroenterology 2014;146:1176-92
SVR12 in genotype 2 and 3 patients on Sofosbuvir+RBV treatment
A. Treatment naïve and experienced, GT 2
B. Treatment naïve and experienced, GT 2, cirrhotics vs non-cirrhotices C. Treatment naïve, GT 3, cirrhotics vs non-corrhotics D. Treatment experienced, GT3, cirrhotics vs non-cirrhotics
Sulkowski MS, et al. N Engl J Med. 2014;370:211-21.
Daclatasvir + Sofosbuvir +/- Ribavirin for HCV GT 1-3 GT1 Treatment-Naïve & Experienced 12 Week Rx: Results
100 100
90 95
0
20
40
60
80
100
DCV + SOF DCV + SOF + RBV DCV + SOF DCV + SOF + RBV
Pati
en
ts w
ith
SV
R12 (
%)
Treatment-Naïve: GT 1a or 1b Treatment-Experienced: GT 1a or 1b
DCV = daclatasvir; SOF = sofosbuvir; RBV = ribavirin
41/41 41/41 19/21 19/20
IFN-free trials for Genotype 1 naïve patients
IFN-free trials for Genotype 1 treatment experienced patients
IFN-free trials for non-Genotype 1 naïve patients
Characteristics needed for future DAAs
Summary
• First-generation PIs have now been replaced
– SMV + P/R x 24 weeks – issue with Q80K in GT1a
– SOF + P/R x 12 weeks in GT1
• IFN will hang around for a short while. . .
– IFN-free therapy coming soon for GT1
• Challenges
– GT1a vs GT1b
– One size fits all vs GT1b regimens
– GT3 may still need IFN, at least for now
• Drawback
– Expensive treatments
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